PROJECT SUMMARY ? Project 2 COCA Project 2 focuses on neuroadaptations and interventions during abstinence from cocaine or heroin self-administration to reverse deficits in the prelimbic (PL) prefrontal cortex that trigger subsequent drug-seeking. A critical issue is to identify the phenotype of the PL neurons that are activated and undergo pro-relapse neuroadaptations in order to reverse them during abstinence and suppress relapse. To accomplish this goal, we will use pathway-specific viral vector and transgenic technology during abstinence from cocaine or heroin self-administration to identify PL neurons projecting to the nucleus accumbens (NA) core that underlie relapse to drug- seeking. A critical feature of cocaine?s and heroin?s effects on PL cortex is that cAMP-dependent protein kinase A (PKA) causes hyper-phosphorylation of AMPA glutamate receptors and pCREB during the first week of abstinence. Our preliminary data indicate that these neuroadaptations are associated with structural changes in perisynaptic processes of PL astrocytes and pyramidal dendritic spines of PL pyramidal neurons that project to the NA core. Further, our data indicate that these changes can be reversed by administration of the procysteine drug, N-acetylcysteine, or the PKA inhibitor, Rp-cAMPs, both of which decrease relapse to drug seeking. These findings will be further investigated by testing the following hypotheses. (1) Abstinence from cocaine and heroin SA will cause increased structural plasticity associated with enhanced plasticity-related protein expression in PL-NA core neurons that express D1 or D2 receptors and these changes will be reversed by relapse to drug seeking. (2) Acute intra-PL PKA inhibition or (3) repeated, systemic NAC injections during abstinence from cocaine or heroin SA will prevent the drug-induced changes in structural and synaptic plasticity. Moreover, preventing structural plasticity will be associated with a decrease in plasticity-related protein expression in PL-NA core neurons that express D1 or D2 receptors and decreased relapse to drug-seeking. This project will discover new relationships between key plasticity- related proteins and structural/synaptic plasticity in a subpopulation of PL-NA core neurons, as well as interactions between PL-NA core neurons and PL astrocytes that may provide new targets for preventing cue-induced cocaine and heroin-seeking.